Future options for ALK-positive non-small cell lung cancer

Iacono, Daniela; Chiari, Rita; Metro, Giulio; Bennati, Chiara; Bellezza, Guido; Cenci, Matteo; Ricciuti, Biagio; Sidoni, Angelo; Baglivo, Sara; Minotti, Vincenzo; Crinò, Lucio

doi:10.1016/j.lungcan.2014.12.017

Cited by 50 publications

(43 citation statements)

References 66 publications

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“…There are currently limited data on the activity of crizotinib in patients with ALK-positive metastatic NSCLC who were first treated with, and had disease progression on, ceritinib or other ALK inhibitors currently under development (22,23). Therefore, future clinical trials should explore the optimal strategy for the initial selection and subsequent sequencing of therapy of ALK inhibitors in patients with ALK-positive metastatic Table 1.…”

Section: Discussionmentioning

confidence: 99%

FDA Approval: Ceritinib for the Treatment of Metastatic Anaplastic Lymphoma Kinase–Positive Non–Small Cell Lung Cancer

Khozin

Blumenthal

Zhang

et al. 2015

Clinical Cancer Research

162

139

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On April 29, 2014, the FDA granted accelerated approval to ceritinib (ZYKADIA; Novartis Pharmaceuticals Corporation), a breakthrough therapy-designated drug, for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive, metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib. The approval was based on a single-arm multicenter trial enrolling 163 patients with metastatic ALK-positive NSCLC who had disease progression on (91%) or intolerance to crizotinib. Patients received ceritinib at a starting dose of 750 mg orally once daily. The objective response rate (ORR) by a blinded independent review committee was 44% (95% CI, 36-52), and the median duration of response (DOR) was 7.1 months. The ORR by investigator assessment was similar. Safety was evaluated in 255 patients. The most common adverse reactions and laboratory abnormalities included diarrhea (86%), nausea (80%), increased alanine transaminase (80%), increased aspartate transaminase (75%), vomiting (60%), increased glucose (49%), and increased lipase (28%). Although 74% of patients required at least one dose reduction or interruption due to adverse reactions, the discontinuation rate due to adverse reactions was low (10%). With this safety profile, the benefit-risk analysis was considered favorable because of the clinically meaningful ORR and DOR.

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Section: Discussionmentioning

confidence: 99%

FDA Approval: Ceritinib for the Treatment of Metastatic Anaplastic Lymphoma Kinase–Positive Non–Small Cell Lung Cancer

Khozin

Blumenthal

Zhang

et al. 2015

Clinical Cancer Research

162

139

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“…Despite novel therapeutic strategies and anticancer agents for lung cancer treatment, the clinical efficacy of these strategies is not optimal and high mortality and poor patient quality of life are problems that remain [3][4][5]. Thus, we need novel lung cancer drugs.…”

Section: Introductionmentioning

confidence: 99%

Toxicarioside H induces drug-resistant mitophagy via promoting expression of sirtuin-3 in lung cancer cells

Huang¹,

Sun²,

Yang³

et al. 2018

Oncotarget

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Cardenolides may have anticancer effects and toxicarioside H (ToxH), which we isolated, may have similar activity but its underlying mechanism against tumors is not clear. Herein, we report that ToxH treatment inhibited cell proliferation and induced mitochondrion-dependent apoptosis and mitophagy in human A549 and H460 lung cancer cells. ToxH treatment increased the expression of Sirt3, and inhibited Sirt3 expression via RNA interference against Sirt3 (siSirt3) suppressed mitophagy in ToxH-treated lung cancer cells. Stronger inhibition of cell proliferation and induction of apoptosis occurred when ToxH-mediated mitophagy was blocked by siSirt3. In addition, ToxH treatment redistributed hexokinase II from the mitochondria to the cytosol in A549 and H460 lung cancer cells, and decreased interaction of hexokinase II with VDAC1 was accompanied by the increased interaction of VDAC1 with parkin. Moreover, the disruption of Sirt3 by siSirt3 decreased the association of VDAC1 with parkin. Thus, ToxH induces drug-resistant mitophagy by enhancing the expression of Sirt3, which leads to the dissociation of hexokinase II from VDAC1 and increased binding of VDAC1 with parkin. Adding ToxH to a mitophagy inhibitor may thus be an effective strategy for treating lung cancer.

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“…In 2007, an oncogenic fusion protein deriving from a rearrangement between the echinoderm microtubule-associated protein-like 4 (EML-4) gene and the ALK gene was first identified in nonsmall cell lung cancer (NSCLC) by Soda et al [1]. Ever since, it became evident that ALK rearrangements are present in 4-5% of patients with NSCLC and consist of either inversions or translocations of exon 20 to 29 of ALK fused to a varying proportion of EML-4 [2]. On this basis, highly effective small molecules ALK-TK inhibitors (-TKIs) have been developed, with crizotinib being the first approved agent by both FDA and EMA for the treatment of ALK-rearranged (ALK-positive), advanced NSCLC [2].…”

mentioning

confidence: 99%

“…Ever since, it became evident that ALK rearrangements are present in 4-5% of patients with NSCLC and consist of either inversions or translocations of exon 20 to 29 of ALK fused to a varying proportion of EML-4 [2]. On this basis, highly effective small molecules ALK-TK inhibitors (-TKIs) have been developed, with crizotinib being the first approved agent by both FDA and EMA for the treatment of ALK-rearranged (ALK-positive), advanced NSCLC [2]. More recently, next-generation ALK-TKIs such as ceritinib and alectinib have demonstrated efficacy in ALK-positive NSCLCs pretreated with crizotinib, which has led to their approval by FDA (ceritinib and alectinib) and EMA (ceritinib) for patients who are resistant or intolerant to crizotinib [3][4][5].…”

mentioning

confidence: 99%

“…Biologically acquired resistance is mediated by a variety of different mechanisms, including secondary mutations within the ALK-TK domain, copy number gains of the ALK fusion gene, and activation of alternative bypass pathways [2]. Importantly, next-generation ALK-TKIs have the potential to overcome the majority of crizotinib-resistant mutations, as well as to inhibit the ALK-TK more potently, which leads to an ORR of approximately 50% in crizotinib-resistant patients [2]. Of note, lorlatinib is a next-generation ALK-TKI that retains potency against all known crizotinib-resistant mutants, and its clinical development is underway [13].…”

mentioning

confidence: 99%

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How might treatment of ALK-positive non-small cell lung cancer change in the near future?

Metro

Bellezza

Puma

et al. 2016

Expert Review of Anticancer Therapy

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Future options for ALK-positive non-small cell lung cancer

Cited by 50 publications

References 66 publications

FDA Approval: Ceritinib for the Treatment of Metastatic Anaplastic Lymphoma Kinase–Positive Non–Small Cell Lung Cancer

FDA Approval: Ceritinib for the Treatment of Metastatic Anaplastic Lymphoma Kinase–Positive Non–Small Cell Lung Cancer

Toxicarioside H induces drug-resistant mitophagy via promoting expression of sirtuin-3 in lung cancer cells

How might treatment of ALK-positive non-small cell lung cancer change in the near future?

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